This is a revised competitive renewal application to conduct a clinical and laboratory investigation aimed at understanding the regulation of cell-mediated immunity (CMI) and how it is subverted in leprosy. The focus of the proposal is on the immunologic mechanisms underlying the long term sequelae and complications of leprosy. The studies will (1) analyze the nature and etiology of the reactional states of leprosy to determine whether genetic polymorphisms and/or bacillary load in the nerves contribute to the development of reversal reactions (RR) and erythema nodosum leprosum (ENL) and whether T cell activation plays a role in the pathogenesis and/or cure of ENL. (2) The proposed studies will examine the process of nerve damage and establish whether it affects cell recruitment and activation and/or poor wound healing in the skin of leprosy patients. A variety of approaches will be used, including genetic analyses involving specific oligonucleotide probing, immunological assays involving cell activation and cytotoxicity as well as cytokine evaluation by ELISA and semiquantitative PCR, and morphologic analyses employing histology, immunocytochemistry, and electron microscopy, to evaluate the nature, interactions and secretory repertoire of the cells involved in the pathobiology of the disease. The studies will be carried out on patient samples and selected patient populations through collaborative efforts in Addis Ababa, Ethiopia and Kathmandu, Nepal. The proposed studies are an extension of the achievements reported in the prior grant period.